Ethanol (EtOH) is abused for both its positive and negative reinforcing effects. Although much is known about the neurobiological substrates underlying EtOH's positive reinforcing effects, relatively little is known about the neurophysiological mechanisms and brain regions that contribute to EtOH's negative reinforcing properties. In this proposal, we take advantage of a genetically engineered mouse line that exhibits increased sensitivity to some of EtOH's negative reinforcing effects. We previously demonstrated that these GABAA receptor alpha1 subunit gene knockin mice exhibit an increase in several measures of acute EtOH-induced anxiolysis and marked increases in EtOH withdrawal seizures. The experiments proposed will integrate neurobiological and behavioral approaches, in global and brain region specific knockin mice, to dissect the mechanisms through which chronic EtOH exposure and withdrawal lead to functional deficits in GABAergic synaptic inhibition. These aims will address the hypothesis that EtOH-induced GABAergic synaptic adaptation in the hippocampus and basolateral amygdala lead to brain-region specific alterations in anxiety-like behavior, withdrawal seizures, and dependence-induced escalations in EtOH drinking. On a more basic level, EtOH alters gene expression. Undoubtedly such EtOH- induced neuroadaptations are also intimately involved in the long-term effects of EtOH on the brain. This is especially true for the transition from recreational drinking to EtOH abuse and alcoholism; the brains of alcoholics have a transcriptome that differs from non-alcoholics. While numerous studies have catalogued changes in EtOH-induced gene expression, a very basic and profound question has not yet been addressed. What is the mechanism by which EtOH reprograms the brain transcriptome? We hypothesize that EtOH-induced epigenetic changes are the fundamental mechanism responsible for this important effect of EtOH. Thus, the final aim will investigate the epigenetic effects of EtOH. PUBLIC HEALTH RELEVANCE: Relevance EtOH addiction remains an imposing medical and socio-economic concern for our society. Elucidating the molecular and neurophysiological substrates that underlie EtOH addiction will facilitate the development of more effective treatment strategies for alcoholism.